Thousands of young adults are diagnosed with relapsing-remitting multiple sclerosis (RRMS) in the United States each year, a life-long neurologic disease leading to cognitive decline in fifty percent of patients within the first few years of diagnosis. RRMS is typically diagnosed between ages 20 and 40, a time when young adults are finishing their education, establishing careers, and raising families. As such, cognitiv decline limits functional independence and reduces quality of life currently and for the rest of their lives. We are unable to predict which RRMS patients will suffer cognitive decline, and, once patients decline, we have no effective treatments for cognitive impairment. As such, the best treatment of cognitive impairment in RRMS patients may be prevention, and prediction is an essential step toward building a science and clinical practice of prevention. Prediction is difficult because patients with similar disease burden often have discrepant outcomes. With the support of my K99/R00 from NICHD/NCMRR, I have shown in several cross-sectional studies that many RRMS patients possess reserve against cognitive decline, afforded either genetically (larger maximal lifetime brain growth [MLBG]) or environmentally (intellectually-enriching experiences). That is, larger MLBG and/or greater intellectual enrichment moderate/attenuate the deleterious effect of MS disease burden (e.g., lesion volume) on cognitive outcomes. Aim 1 is the first longitudinal study to examine whether larger MLBG and greater intellectual enrichment protect against cognitive decline in RRMS patients. Our results will identify MLBG and intellectual enrichment as cost-effective, safe, and easily-acquired markers of future cognitive decline in RRMS, which will improve prediction of cognitive decline clinically (guiding early intervention), and facilitate the identification of at-risk patients for prevention research. [MLBG and lifetime enrichment (estimated with vocabulary) will help predict future cognitive decline, but both are outside one's current control. Aim 2 will (a) investigate whether a current cognitively-stimulating lifestyle (e.g., reading, hobbies) independently lowers risk for cognitive decline, (b) identify which types of leisure are most protective against decline in cognitive efficiency and memory, respectively, and (c) examine neuroanatomical substrates for reserve against cognitive decline. Aim 2 will inform the development and evaluation of early interventions to build reserve.] Aim 3 will use functional MRI to identify specific patterns of current (baseline) brain function linked to cognitive preservation over time. Such markers can be used as benchmarks of success in early intervention / prevention research. Rather than waiting years to learn if an intervention successfully prevented decline, one can evaluate whether an intervention altered brain activity to more closely match a pattern linked to cognitive preservation. Results of this R01 will improve prediction of cognitive decline in RRMS patients, and [lay the groundwork for the development of evidence-based early interventions to build reserve in RRMS. Our team of investigators has the experience, expertise, and resources to successfully complete this large-scale and important R01 project.]